TAS1553, a small molecule subunit interaction inhibitor of ribonucleotide reductase, exhibits antitumor activity by causing DNA replication stress

Ribonucleotide reductase (RNR) is composed of two non-identical subunits, R1 and R2, and plays a crucial role in balancing the cellular dNTP pool, establishing it as an attractive cancer target. Herein, we report the discovery of a highly potent and selective small-molecule inhibitor, TAS1553, targeting protein-protein interaction between R1 and R2. TAS1553 is also expected to demonstrate superior selectivity because it does not directly target free radical or a substrate binding site. TAS1553 has shown antiproliferative activity in human cancer cell lines, dramatically reducing the intracellular dATP pool and causing DNA replication stress. Furthermore, we identified SLFN11 as a biomarker that predicts the cytotoxic effect of TAS1553. Oral administration of TAS1553 demonstrated robust antitumor efficacy against both hematological and solid cancer xenograft tumors and also provided a significant survival benefit in an acute myelogenous leukemia model. Our findings strongly support the evaluation of TAS1553 in clinical trials.


H NMR(400 MHz)spectrum of TAS1553
The 1 H NMR(400 MHz)spectrum of TAS1553 in CD3OD was presented.

C NMR(100 MHz)spectrum of TAS1553
The 13 C NMR(100 MHz)spectrum of TAS1553 in CD3OD was presented.

HRESIMS of TAS1553
The result showed the HRESIMS of TAS1553

HRESIMS of compound 1
The result showed the HRESIMS of compound 1

Synthesis of TAS1553
TAS1553 was synthesized by a multi-step reaction. The detailed reaction schemes are as follows: Step 1 After dropping a diethyl ether solution of methylmagnesium bromide (3.0 M, 3.2 mL, 9.6 mmol) to a THF solution (10 mL) of 6-fluoro-2,3-dimethyl-benzaldehyde (1.4g, 9.2 mmol) at 0 °C, the reaction mixture was stirred at room temperature for 30 minutes . A saturated aqueous ammonium chloride solution was added dropwise, and ethyl acetate was added, and the resultant was separated into different layers. The organic layer was successively washed with saline, and then dried over anhydrous sodium sulfate. After extracted solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent:Hexane/EtOAc = 70/30) to obtain 1.5g (98%) of 1-(6-fluoro-2,3 dimethylphenyl)ethan-1-ol as a light yellow oil.
Phosphorus tribromide (14 mL, 149 mmol) was added dropwise at 0 °C to a chloroform solution (100 mL) of 1-(6-fluoro-2,3-dimethylphenyl)ethan-1-ol (12 g, 71.3 mmol) , and the reaction solution was stirred for 30 minutes at 0 °C. The reaction mixture was added to an ice-cold saturated aqueous sodium bicarbonate. After chloroform was added to the mixture, the resultant was separated into different layers, and the organic layer was successively washed with saline. The organic layer was dried over anhydrous sodium sulfate to obtain 16.5 g (quant.) by concentrating under reduced pressure. acetate were added to the reaction solution, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed successively with water, saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hexane/EtOAc = 5/95) to obtain 11.8 g (50%) as a red solid.

Synthesis of compound 1
Compound 1 was synthesized by a multi-step reaction. The detailed reaction schemes are as follows: Step 1 A DMF solution (85 mL) of 1-(1-bromoethyl)naphthalene (4.2 g, 17.7 mmol) was added dropwise to a DMF solution (40 mL) of [(2S)-1-benzylpyrrolidine-2-carbonyl]-{2-[N-(carboxymethyl)-C-phenylcarbonimidoyl]phenyl}azanide;nickel (4.0 g, 8.0 mmol), and powder sodium hydroxide (3.2 g, 80.3 mmol), and the mixture was stirred for 1 hour at 0 °C. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-80 % EtOAc in Hexane) to obtain 2.3 g (44%) as a red solid.